WO2012062229A1 - A method of manufacturing (-)-l-(3-hydroxypropyl)-5-[(2r)-2-({2,2,2-trifluoroethoxy)- phenoxyethyl}amino)propyl]-2,3-dihydro-lh-indole-7-carboxamide - Google Patents

Abstract

A method of manufacturing optically pure or optically enriched silodosin of formula I and of its pharmaceutically acceptable salts, in which a secondary amine of general formula II, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group, (a) is N-alkylated with an alkylating agent of general formula III, wherein X denotes a good leaving group, such as a halogen or an alkane sulfonyloxyl group RS0₂0 or an arene SLilfonyloxyl group ArS0₂0, R means an alkyl group with 1 to 4 carbon atoms and Ar is a substituted or unsubstituted phenyl group; (b) the obtained tertiary amine of general formula IV, wherein Bn is as defined above, is hydrogenolyzed with hydrogen on a metal catalyst; (c) and the resulting nitrile of formula V, wherein Bn is as defined above, is hydrolyzed by treatment with alkaline agents; and optionally, (d) additional O-debenzylation of the amide-ether of general formula VI, wherein Bn is as defined above, with dealkylating agents is carried out; and, if desired, the obtained silodosin is transformed to the respective salts by treatment with pharmaceutically acceptable acids.

Description

A method of manufacturing (-)-l-(3-hydroxypropyl)-5-[(2R)-2-({2,2,2-trifluoroethoxy)- phenoxyethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide

Technical Field

The invention relates to a method of manufacturing (-)-l-(3-hydroxypropyl)-5-[(2 ?)-2- ( {2,2,2-trifluoroethoxy)phenoxyethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide of formula I

also known under the name silodosin, and of its salts.

Background Art Silodosin of formula I, also known under the indication KMD-3213, or chemically (-)-

1 -(3-hydroxypropyl)-5-[(2i?)-2-( {2,2,2-trifluorethoxy)phenoxyethyl} amino)propyl]-2,3- dihydro-lH-indole-7-carboxamide, is a highly selective antagonist of l-adrenoreceptors, suppressing urinary duct contractions, and exhibiting a minimal drop of blood pressure at the same time. It has been developed in the form of the ( ?)-enantiomer by the Japanese company Kissei Pharmaceutical for treatment of benign prostatic hyperplasia (BPH).

According to the original method described in the patent document EP 0 600 675 (Kissei Pharmaceutical) racemic silodosin is produced using a multi-step method from N- acetylindoline, which is transformed to the 5-(2-brompropionyl)-derivative either by direct acylation with a bromopropionyl halide or in two steps by acylation with propionyl chloride and subsequent bromination. Deoxygenation by means of triethyl silane is followed by nitration into the aromatic ring (HN0₃); the nitro compound is then converted to a cyano derivative by reduction (hydrogenation on PtC^), diazotization and subsequent reaction of the diazonium salt with copper cyanide. The thus obtained N-acetyl-7-cyano-5-(2- bromopropyl)benzene (A) is then converted in two steps into a primary amine first by substitution with sodium azide and then by hydrogenation of the azide on Pd/BaS0₄. Introduction of the 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl group to the nitrogen is performed by alkylation of the primary amine by means of alkylating agents B derived from 2- [2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (bromide, mesylate, etc.).

The same secondary amine C is alternatively produced by alkylation of 2-[2-(2,2,2- trifluoroethoxy)phenoxy]-ethylamine with the bromide A. Resolution of the racemic amine C is carried out using the low-efficiency formation of salts with (+)-mandelic acid.

Amine C is further transformed to an N-Boc-derivative (Boc is a short for tert- butoxycarbonyl derivatives (Boc₂0)), which is then subjected to alkaline N-deacetylation producing an N-nor-amine. Then, the nitrile is hydrolyzed to the corresponding carboxamide by means of a peroxide in an alkaline environment and the obtained indoline is N-alkylated with 3-ier/-butyldimethylsilyloxypropylalcohol nosylate. Finally, the synthesis is completed by deprotection; first, the TBS-group is eliminated by treatment with tetrabutylammonium fluoride, and then trifluoroacetic acid is used to deprotect the amine, producing silodosin. A disadvantage consists in the use of a multi-step method, in which the optical resolution is applied first at an advanced step.

The method according to patent JP 2002265444 (Kissei Pharmaceutical) describes production of optically active silodosin, which starts by resolution of 3-[N-(3- benzyloxypropyl)-7-cyanphenyl]-2-methylpropanoic acid by means of a salt with {\S,2R)-2- benzylaminocyclohexylmethanol. The obtained (i?)-acid (activation with Im₂CO) is transformed to an amide, which is subjected to Hofmann degradation (NaOCl), producing N- acetyl-7-cyano-5-(2-aminopropyl)benzene C. The latter is alkylated with 3-benzyloxypropanol triflate, followed by hydrolysis with an alkali peroxide to transform the nitrile into an amide, and the whole process is completed with hydrogenolytic debenzylation on palladium. A disadvantage of this method consists in relatively low efficiency of the resolution of the acid.

The method according to patent JP 2006188470 (Kissei Pharmaceutical; Asahi Glass) starts from optically active O,N-protected N-(3-hydroxypropyl)-5-(2-amino-l-oxopropyl)- indoline, which is first transformed into a primary amine carbamate by reduction of the carbonyl oxygen; its bromination in position 7 and subsequent substitution with CuCN results in production of a nitrile. Next, N-deprotection and then alkylation of the released primary amine with an alkylating agent X follows. Finally, silodosin is produced by O-deprotection and a final hydrolysis of the nitrile to the carboxamide. A disadvantage of this method is the risk of racemization of the starting amino ketone, as well as occurrence of impurities due to over-alkylation of the amine. According to the method of patent EP 1 806 340 (WO2006046499, Kissei Pharmaceutical) silodosin (I) is produced from 3-[5-((2/?)-2-aminopropyl-7-cyanoindolin-l - yl]propanol benzoate, which is alkylated with 2-[2-(2,2,2-trifluoroethoxy)phenyloxy]ethanol mesylate, producing a secondary base, which is depleted of the over-alkylated product in the form of a salt with oxalic acid, then the ester is subjected to alkaline hydrolysis and the synthesis is completed by treatment with an alkali peroxide, resulting in transformation of the nitrile to an amide. This method also manifests the disadvantage that over-alkylated impurities are produced, which have to be subsequently eliminated.

In the method of patent CN 101302183 (China Pharmaceutical University) N-Boc- protected silodosin, t-butyl-[(l ?)-2-[7-(aminocarbonyl)-l-(3-hydroxypropyl)indolin-5-yl]-l - methylethyl][2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]-carbamate, is produced by alkylation of ?-butyl-(i?)-[2-[7-(aminocarbonyl)indolin-5-yl]-l-methylethyl][2-[2-(2,2,2-trifluoroethoxy)- phenoxy]ethyl]-carbamate with 3-iodopropanol in the presence of Na₂C0₃ and 18-crown-6. Disclosure of Invention

The invention provides a new efficient method of manufacturing silodosin of formula I

wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group, is N-alkylated with an alkylating agent of eneral formula III

(III) wherein X denotes a good leaving group, such as a halogen or an alkane sulfonyloxyl group RS0₂0 or an arene sulfonyloxyl group ArS0₂0, R means an alkyl group with 1 to 4 carbon atoms and Ar is a substituted or unsubstituted phenyl group; the obtained tertiary amine of general formula IV

wherein Bn is as defined above,

is hydrogenolyzed with hydrogen on a metal catalyst; and the resulting nitrile of formula V

wherein Bn is as defined above,

is hydrolyzed by treatment with alkaline agents; optionally, additional O-debenzylation of the amide-ether of general formula VI

wherein Bn is as defined above,

with dealkylating agents is carried out; and, if desired, the obtained silodosin is transformed to the respective salts by treatment with pharmaceutically acceptable acids.

The invention also provides key intermediates of formulae II

and IV

wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group.

Detailed description of the invention

More specifically, the invention provides a method of manufacturing optically pure or optically enriched silodosin of formula I

and of its pharmaceutically acceptable salts,

in which a secondary amine of general formula II

wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group,

is

yV-alkylated with an alkylatin agent of general formula III

(III) wherein X denotes a good leaving group, such as a halogen or an alkane sulfonyloxyl group RS0₂0 or an arene sulfonyloxyl group ArS0₂0, R means an alkyl group with 1 to 4 carbon atoms and Ar is a substituted or unsubstituted phenyl group;

in the presence of a base, in an inert organic solvent (Step A); the obtained tertiary amine of general formula IV

wherein Bn is as defined above,

is selectively N-hydrogenolyzed with hydrogen on a metal catalyst at a pressure of 0.1-5 MPa or by means of ammonium formate, in an inert organic solvent (Step B);

wherein Bn is as defined above,

is hydrolyzed by treatment with alkaline agents (Step C); and, finally, the amide-ether of g

wherein Bn is as defined above,

is subjected to O-debenzylation with hydrogenolytic or trialkylhalide dealkylating agents (Step D); and, if desired, the obtained silodosin is transformed to the respective salts by treatment with pharmaceutically acceptable acids.

We have found out that optically pure or optically enriched silodosin of formula I can, efficiently and in high purity, be manufactured by an asymmetrical method, which ensures production efficiency and high optical purity of the intermediates, and also prevents formation of twice N-alkylated amines as side products of the alkylation. The process of manufacturing silodosin from the secondary amine of general formula II comprises the following four synthetic steps:

Step A. Alkylation of the amine of general formula II, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4- methoxybenzyl, or the benzhydryl or trityl group, is carried out by reaction with an alkylating agent of general formula III, wherein X stands for a good leaving group, such as a halogen or an alkane sulfonyloxyl group or an arene sulfonyloxyl group. Useful halides include a iodide, bromide or chloride. In another embodiment an alkane sulfonyl group, such as e.g. methane sulfonyl group, or an arene sulfonyl group, such as benzene sulfonyl group or para-toluene sulfonyl group, can be used. The alkylating agent is used in an amount of 1 to 7 equivalents, preferably 1.5 to 4 equivalents, in the presence of a base. Useful bases include inorganic bases, e.g. potassium or sodium carbonate, or hindered organic bases, such as diisopropylethylamine, in an amount of 0.5 to 8 equivalents, preferably 1 to 5 equivalents. The alkylation is carried out in an inert organic solvent, such as carboxamides, e.g. dimethyl formamide, dimethyl acetamide, or N-methyl pyrrolidone, or alcohols, e.g. ethanol, or dimethyl sulfoxide, in the temperature range from 50°C to the boiling point of the mixture, preferably at 75 to 125°C.

In a preferred embodiment a chloride, bromide, alkane sulfonate or arene sulfonate is used in the presence of an alkali metal iodide, e.g. sodium or potassium iodide, in an amount of 0.1 to 2 equivalents, commonly 0.5 to 1.1 equivalents, and the reaction is performed in dimethyl formamide at a temperature of 95 to 125°C. In an especially preferred embodiment the alkylating agent and/or also the base is added in portions in the course of the reaction.

Step B. The removal of the chiral 1 -phenylethyl group in the compound of general formula IV, wherein Bn is as defined above, is carried out by hydrogenolysis with hydrogen on metal catalysts, such as palladium. Gaseous hydrogen is used, or, alternatively, the hydrogenolysis is carried out by means of ammonium formate. The hydrogenolysis is carried out in an inert organic solvent, such as in lower alcohols, e.g. in methanol, ethanol or isopropyl alcohol, or in cyclic ethers, such as tetrahydrofuran or 1,4-dioxane, or in ethyl acetate, or in their mixtures, at a pressure of 0.1 to 5 MPa in the temperature range of 10 to 60°C, preferably 20 to 40°C.

In a preferred embodiment, e.g., hydrogen on Pd/C is used in the environment of an alcohol, e.g. methanol or ethanol, or their mixtures with water, at a pressure of 0.1 to 3 MPa.

Step C. Transformation of the nitrile group in the compound of formula V, wherein Bn is as defined above, to the carboxamide group is carried out by means of alkaline agents such as alkali metal hydroxides, e.g. sodium or potassium hydroxide, in polar solvents such as methanol, ethanol or dimethyl sulfoxide, at a temperature from -10°C to the boiling point of the mixture. The process is preferably performed with alkali hydroxides in the presence of hydrogen peroxide in dimethyl sulfoxide at a temperature of -10 to 100°C, preferably in the range of 0 to 40°C.

Step D. Deprotection of the O-benzyl protective group in the compound of general formula VI, wherein Bn is as defined above, is carried out by dealkylation processes by means of deprotecting agents such as hydrogenolytic agents or trialkyl silyl halide agents. Useful hydrogenolytic agents include hydrogen on a metal catalyst, e.g. on palladium or platinum, in inert solvents, e.g. ethanol, methanol, 2-methyltetrahydrofuran or tetrahydrofuran, ethyl acetate, or in their mixtures, in the temperature range of 10 to 50°C. Useful trialkyl silyl halide agents include e.g. trimethyl silyl iodide in an inert solvent, e.g. in dichloromethane, chloroform, or toluene, in the temperature range of -5 to + 40°C, preferably in the temperature range from 5 to 25 °C.

In a preferred embodiment hydrogen on Pd/C is used in the environment of an alcohol, e.g. methanol or ethanol, or ethyl acetate, or their mixtures. In another preferred embodiment the deprotection is carried out with trimethyl silyl iodide in dichloromethane in the temperature range of 5 to 25 °C.

The obtained compound of formula I (silodosin) is finally purified by crystallization from a suitable organic solvent or mixture of solvents, e.g. ethyl acetate, 2-propanol or methanol. If desired, the obtained silodosin is converted to the corresponding salt by treatment with pharmaceutically acceptable acids.

In another aspect, the invention provides a method of manufacturing silodosin using the same above-mentioned key intermediates II and IV by a method comprising the following steps:

Step A - N-alkylation of a secondary amine of general formula II

wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group

with an alkylating agent of general formula III

(ill) wherein X denotes a good leaving group, such as a halogen or an alkane sulfonyloxyl group RSO₂O or an arene sulfonyloxyl group ArS0₂0, R means an alkyl group with 1 to 4 carbon atoms and Ar is a substituted or unsubstituted phenyl group,

in the presence of a base, in an inert organic solvent selected form the group including carboxamides, N-methyl pyrrolidone, lower alcohols and dimethyl sulfoxide, at the temperatures of from 50°C to the boiling point of the mixture, in the presence or absence of an alkali metal iodide;

Step B - subjecting the obtained tertiary amine of general formula IV

wherein Bn is as defined above,

to 0,./V-hydrogenolysis with hydrogen on a metal catalyst in the presence of strong acids, such as hydrochloric acid, sulfuric acid or methanesulfonic acid, at a pressure of from 0.1 to 5 MPa in an inert organic solvent;

Step C - subjecting the resulting nitrile of formula V

to hydrolysis by treatment with alkali metal hydroxides, optionally in the presence of hydrogen peroxide in polar solvents such as methanol, ethanol., glyme or diglyme, or dimethyl sulfoxide, at a temperature of from -10°C to the boiling point of the mixture; and, optionally converting to the respective salts by treating with pharmaceutically acceptable acids.

Step A. Alkylation of the amine of general formula II, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4- methoxybenzyl, or the benzhydryl or trityl group, is carried out by reaction with an alkylating agent of general formula III, wherein X stands for a good leaving group, such as a halogen or an alkane sulfonyloxy group or an arene sulfonyloxy group. Useful halides include a iodide, bromide or chloride. In another embodiment an alkane sulfonyloxyl group, such as e.g. methane sulfonyloxyl group, or an arene sulfonyloxyl group, such as benzene sulfonyloxyl group or para-toluene sulfonyloxyl group, can be used. The alkylating agent is used in an amount of 1 to 7 equivalents, preferably 1.5 to 4 equivalents, in the presence of a base. Useful bases include inorganic bases, e.g. potassium or sodium carbonate, or hindered organic bases, such as diisopropylethylamine, in an amount of 0.5 to 8 equivalents, preferably 1 to 5 equivalents. The alkylation is carried out in an inert organic solvent, such as carboxamides, e.g. dimethyl formamide, dimethyl acetamide, or N-methyl pyrrolidone, or alcohols, e.g. ethanol, or dimethyl sulfoxide, in the temperature range from 50°C to the boiling point of the mixture, preferably at 75 to 125°C.

In a preferred embodiment a chloride, bromide, alkane sulfonate or arene sulfonate is used in the presence of an alkali metal iodide, e.g. sodium or potassium iodide, in an amount of 0.1 to 2 equivalents, commonly 0.5 to 1.1 equivalents, and the reaction is performed in dimethyl formamide at a temperature of 95 to 125°C. In an especially preferred embodiment the alkylating agent and/or also the base is added in portions in the course of the reaction.

Step B. The simultaneous removal of the chiral 1 -phenyl ethyl group and of the benzyl in the compound of general formula IV is carried out by hydrogenolysis with hydrogen on metal catalysts, such as palladium. The hydrogenolysis is carried out in the presence of strong acids, such as hydrochloric acid, sulfuric acid, or methane sulfonic acid, in an inert organic solvent, such as in lower alcohols, e.g. in methanol, ethanol or isopropyl alcohol, or in cyclic ethers, such as tetrahydrofuran or 1 ,4-dioxane, or in ethyl acetate, or in their mixtures, at a pressure of 0.1 to 5 MPa in the temperature range of 10 to 60°C, preferably 20 to 40°C.

In a preferred embodiment, e.g., hydrogen on Pd/C is used in the presence of hydrochloric or sulfuric acid in the environment of an alcohol, e.g. methanol or ethanol, or their mixtures with water, at a pressure of 0.1 to 2 MPa.

Step C. Transformation of the nitrile group in the compound of formula V to the carboxamide group is carried out by means of alkaline agents such as alkali metal hydroxides, e.g. sodium or potassium hydroxide, in polar solvents such as methanol, ethanol or dimethyl sulfoxide, at a temperature from -10°C to the boiling point of the mixture. The process is preferably performed with alkali hydroxides in the presence of hydrogen peroxide in dimethyl sulfoxide at a temperature of -10 to 100°C, preferably in the range of 0 to 40°C.

The obtained compound of formula I (silodosin) is finally purified by crystallization from a suitable organic solvent or mixture of solvents, e.g. ethyl acetate, 2-propanol or methanol. If necessary, the obtained silodosin is converted to the corresponding salt by treatment with pharmaceutically acceptable acids.

The method in accordance with the invention comprises, as the key step, preparation of an optically pure or optically enriched tertiary amine of general formula IV

wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group,

in which a secondary amine of general formula II

wherein Bn is as defined above,

is N-alkylated with an alkylating agent of eneral formula III

wherein X stands for a good leaving group, such as a halogen or alkane sulfonyloxyl group RS0₂0 or arene sulfonyloxyl group ArS0₂0, R stands for an alkyl group with 1 to 4 carbon atoms and Ar is a substituted or unsubstituted phenyl group. The starting optically pure or optically enriched secondary amine of general formula II

wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group.

is preferably prepared by a method, in which a ketone of general formula VII

wherein Bn is as defined above,

is subjected to diastereoselective reductive amination with the (i?)-amine of formula VIII

The method of preparing the amine of formula II consists in subjecting the ketone of general formula VII, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group, to diastereoselective reductive amination with the (7?)-amine of formula VIII, which is used in an amount of 0.9 to 1.5 equivalents, preferably 1 to 1.1 equivalents. A necessary precondition for the success of the process is the presence of a Lewis acid, e.g. titanium tetraisopropoxide, or a Bronsted acid such as benzoic acid or an aliphatic carboxylic acid such as acetic acid. These acids are used in amounts of 0.1 to 3 equivalents, preferably 0.5 to 1.3 equivalents. The reductive amination is carried out in the environment of hydrogen and a metal catalyst in an inert organic solvent in the temperature range from 0°C to the boiling point of the mixture, preferably at 20 to 40°C. The reaction is carried out in an inert organic solvent such as cyclic ethers, e.g. tetrahydrofuran, 2-methyltetrahydrofuran or 1 ,4-dioxane, or their mixtures.

In a preferred embodiment the reductive amination is carried out by hydrogen in the presence of benzoic acid under the presence of an Adams' catalyst in tetrahydrofuran, 2- methyltetrahydrofuran or dioxane at a temperature of 20 to 35°C.

l-[3-(Benzyloxy)propyl]-5-[(2/?)-2-{[(li?)-l-phenylethyl]amino}propyl]indoline-7- carbonitriles of general formula II are new compounds representing key intermediates in the synthesis of pure silodosin. This opinion is based on the experimental finding that the secondary amines of general formula II are sterically hindered, and hence their alkylation does not result information of over-alkylated side products.

This invention further provides a method of preparing an optically pure or optically enriched secondary amine of general formula II

wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group,

wherein an aldehyde of general formula IX

wherein Bn is as defined above, is brominated with bromine (step 1); the obtained bromide of general formula X

wherein Bn is as defined above,

is cyanized with cyanides in polar organic solvents selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone or dimethyl sulfoxide, in the temperature range from 60°C to the boiling point of the mixture (step 2); the prepared cyano-aldehyde of general formula XI

wherein Bn is as defined above,

is condensed with nitroethane in the presence of a slightly basic catalyst in the presence or absence of an organic solvent in the temperature range of 0 to 40°C (step 3); the produced nitrostyrene of general formula XII

wherein Bn is as defined above,

is subjected to reductive hydrolysis with metals in a strongly acidic environment of a mineral acid, such as hydrochloric or sulfuric acid, preferably in the presence of metallic ions in the temperature range of 30 to 100°C (step 4); and, finally, the ketone of general formula VII

wherein Bn is as defined above,

is subjected to se diastereoselective reductive amination with (i?)-amine of formula VIII

in an amount of 0.9 to 1.5 equivalents, preferably 0.95 to 1.1 equivalents, by treatment with hydrogen on a metal catalyst in the presence of a Bronsted acid in an inert organic solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran or 1 ,4-dioxane or their mixture, in the temperature range from 0°C to the boiling point of the mixture (step 5). The method of obtaining the secondary amine of general formula II, optically pure, or optically enriched, starts with the aldehyde of general formula IX and comprises the following steps:

Step 1 : Preparation of a 7-bromo-derivative of general formula X, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4- methoxybenzyl, or the benzhydryl or trityl group, in which the starting compound of general formula IV, wherein Bn is as defined above, is brominated with molecular bromine in a slightly acidic environment, e.g. in the presence of acetic acid, in the presence or absence of an inert organic solvent, e.g. dichloromethane, chloroform, in the temperature range from 0°C to the boiling point of the mixture, preferably in the range of 10 to 35°C.

In a preferred embodiment step 1 is carried out with bromine in an acetic acid environment in the temperature range of 5 to 35°C. Step 2: The conversion of the bromide of general formula X to the nitrile of formula XI, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group, is carried out with cyanides, specifically by treatment with copper cyanide in polar organic solvents, e.g. dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone or dimethyl sulfoxide, in the temperature range from 60°C to the boiling point of the mixture, preferably at from 90°C to 160°C.

This method is preferably performed by heating of the bromide of general formula X with copper cyanide in dimethyl formamide to the temperature of from 1 10°C to the boiling point of the mixture.

Step 3: The method of preparing the nitrostyrene of general formula XII, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4- methoxybenzyl, or the benzhydryl or trityl group, is carried out by condensation of the aldehyde of general formula XI, wherein Bn has the above mentioned meaning, with nitroethane, in the presence of a slightly alkaline catalyst, e.g. ammonium acetate, in the presence or absence of an organic solvent, e.g. methanol or ethanol, in the temperature range of 0°C to 40°C.

This method is preferably performed by condensation of the aldehyde of general formula XI with an excess of nitroethane and in the presence of ammonium acetate, without an organic solvent.

Step 4: Reductive hydrolysis of the nitrostyrene of general formula XII to the ketone of general formula VII, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group, is carried out with metals, e.g. iron, in a strongly acidic environment of a mineral acid, e.g. hydrochloric acid or sulfuric acid, preferably in the presence of metallic ions, in the temperature range of 30°C to 100°C.

This method is preferably carried out by heating of the nitrostyrene of general formula XII with iron, with addition of a catalytic amount of an iron salt, e.g. iron trichloride, in the environment of hydrochloric acid. Step 5: The method of preparing the secondary amine of formula II, wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4- methoxybenzyl, or the benzhydryl or trityl group, consists in subjecting the ketone of general formula VII, wherein Bn is as defined above, to diastereoselective reductive amination with the (^)-amine of formula VIII, which is used in an amount of 0.9 to 1.5 equivalents, preferably 1 to 1.1 equivalents. A necessary precondition for the result of the process is the presence of a Lewis acid, e.g. titanium tetraisopropoxide, or a Bronsted acid such as an arene carboxylic acid, e.g. benzoic acid, 4-methylbenzoic or 3-methoxybenzoic acids, or aliphatic carboxylic acids, e.g. acetic acid. These acids are used in amounts of 0.1 to 3 equivalents, preferably 0.5 to 1.3 equivalents. The reductive amination is carried out in the environment of hydrogen and a metal catalyst in an inert organic solvent in the temperature range from 0°C to the boiling point of the mixture, preferably 20 to 40°C. The reaction is performed in an inert organic solvent such as a cyclic ether, e.g. tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane, or their mixtures.

In a preferred embodiment the reductive amination is carried out in the presence of benzoic acid with hydrogen in the presence of an Adams' catalyst in tetrahydrofuran, 2-methyltetrahydrofuran or dioxane at a temperature of from 20 to 35°C.

The examples below illustrate, but do not limit in any way, the general principles of the production method in accordance with the invention.

Examples

Example 1

Preparation of the compound of formula I (silodosin; l-(3-hydroxy- propyl)-5-[(2/?)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-indoline-7- carboxamide)

38 mg (0,06 mmol) of l-[3-(benzyloxy)propyl]-5-[(2i?)-2-({2-[2-(2,2,2-trifluoroethoxy)- phenoxy]ethyl}amino)propyl]indoline-7-carboxamide (general formula VI: Bn = PhCH₂) are dissolved in 1 ml of dry dichloromethane, 0.02 ml (0.14 mmol) of trimethyl silyl iodide are added to the solution dropwise in an inert atmosphere. After stirring at the laboratory temperature for 30 min the reaction is quenched by addition of 0.02 ml (0.49 mmol) of methanol. After evaporation of the solvent the mixture is partitioned between water (5 ml) and ethyl acetate (5 ml). The aqueous layer is further shaken with ethyl acetate (2x 5 ml). The combined organic fractions are washed with a saturated solution of sodium pyrosulfite (3 ml), a saturated solution of sodium hydrogen carbonate (3 ml) and brine (3 ml). After drying with anhydrous sodium sulfate and evaporation of the solvent 21 mg (0.04 mmol) of the product in the form of a semi-solid oil are obtained. After re-dissolution in 0.5 ml of ethyl acetate and cooling silodosin (formula I) crystallizes (melting point 99.1 to 101.6 °C).

'H-NMR (CDC1₃) δ 1.07 (3H, d, J=6.2 Hz), 1.79 (2H, pent., J=6.1 Hz), 2.33 (bs), 2.52 (l H, dd, J=6.8, 13.5 Hz), 2.68 (1H, dd, J=6.5,13.5 Hz), 2.93-3.10 (5H, m), 3.18 (2H, t, J=6.8 Hz), 3.41 (2H, t, J=8.7 Hz), 3.73 (2H, t, J- 5.6 Hz), 4.06-4.12 (2H, m), 4.3 (2H, q, J=8.4 Hz), 6.12 (bs), 6.73 (bs), 6.88-7.06 (5H, m), 7.17 (1H, s).

Example 2

Preparation of the compound of general formula VI: Bn = PhCH₂ (l-[3-(benzyloxy)propyl]- 5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl]indoline-7- carboxamide)

60 mg (0.1 1 mmol) of l-[3-(benzyloxy)propyl]-5-[(2i?)-2-({2-[2-(2,2,2-trifluoromethoxy)- phenoxyjethyl} amino )propyl]indoline-7-carbonitrile (general formula V: Bn = PhCH₂) are dissolved in 3 ml of dimethyl sulfoxide and 0.15 ml of a 5M sodium hydroxide solution are added in a nitrogen atmosphere. The mixture is cooled in an ice bath and 0.15 ml (1.5 mmol) of 30% hydrogen peroxide are added dropwise under cooling. The mixture is stirred in an ice bath for 10 min, then at the laboratory temperature for 20 h. A solution of sodium pyrosulfite (75 mg, 0.4 mmol) in 3 ml of water is then added to the mixture; after stirring for 10 minutes it is extracted with ethyl acetate (3 x 5 ml) and the combined organic fractions are washed with water (2 x 3 ml). Evaporating the solvent offers 50 mg (0.09 mmol) of the raw product as an orange oil.

'H-NMR (CDC1₃) <Π .06 (3H, d, J=6.2), 1.85-1.91 (2H, m), 2.51 (1H, dd, J=7.1,13.5 Hz), 2.72 ( 1H, dd, J=6.2,13.5 Hz), 2.93-3.04 (5H, m), 3.11-3.17 (2H, m), 3.44 (2H, t, J= 8.3 Hz), 3.51 (2H, t, J=6.2 Hz), 4.06-4.09 (2H, m), 4.31 (2H, q, J=8.4 Hz), 4.47 (2H, s), 5.61 (bs), 6.89-7.05 (5H, m), 7.28-7.35 (6H, m). Example 3

Preparation of the compound of general formula V: Bn = PhCH₂ (l-[3-(benzyloxy)propyl]-5- [(2/?)-2-( {2-[2-(2,2,2-trifluoroethoxy)-phenoxy]ethyl}amino)propyl]indoline-7-carbonitrile) Process (a):

124 mg (0.18 mmol) of l-[3-(benzyloxy)propyl]-5-[(2/?)-2-([(lR)-l-phenylethyl] {2,2,2- trifluoroethoxy)phenoxy]ethyl}amino)propyl]indoline-7-carbonitrile (general formula IV: Bn = PhCH₂) are dissolved in 4 ml of ethanol and 54 mg of 5% Pd/C are added. The apparatus is rinsed with hydrogen 3 times and then hydrogenated at the pressure of 1.2 MPa and temperature of 50°C for 19 hours. After removal of the catalyst by filtration and evaporation of the solvent 97 mg (0.17 mmol) of the raw product are obtained.

Ή-NMR (CDC1₃) 0.99 (3H, d, J=6.2 Hz), 1.87-1.96 (2H, m), 2.35 (1H, dd, J-7.0,13.6 Hz), 2.55 (1H, dd, J=6.3,13.6 Hz), 2.79-3.00 (5H, m), 3.42-3.61 (6H, m), 4.00-4.06 (2H, m), 4.25 (2H, q, J=8.4 Hz), 4.44 (2H, s), 6.81-6.96 (6H, m), 7.18-7.27 (5H, m).

Process (b):

30 mg (0.04 mmol) of l-[3-(benzyloxy)propyl]-5-[(2R)-2-([(l ?)-l-phenylethyl] {2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl}amino)propyl]indoline-7-carbonitrile (general formula IV: Bn = PhCH₂) are dissolved in 3 ml of ethanol, 0.1 ml of IN hydrochloric acid and 25 mg of 10% Pd/C are added. The hydrogenation vessel is rinsed with hydrogen three times and then hydrogenation is carried out under slight overpressure and at the laboratory temperature for 4 hours. After the removal of the catalyst by filtration and evaporation of the solvent the evaporation residue is partitioned between water and ethyl acetate; the separated aqueous layer is alkalized and then extracted with ethyl acetate. The raw product (14 mg, 0.03 mmol) is obtained by evaporation in vacuo as a yellowish oil.

Ή-NMR (CDCI3) δ 1.05 (3H, d, J=6.3 Hz), 1.89-1.95 (2H, m), 2.16 (bs), 2.43 (lH, dd, J=7.0, 13.6 Hz), 2.62 (1H, dd, J=6.3, 13.6 Hz), 2.87-3.05 (5H, m), 3.56 (2H, t, J=8.7 Hz), 3.66 (2H, t, J=7.2 Hz), 3.80 (2H, t, J=6.0 Hz), 4.07-4.12 (2H, m), 4.32 (2H, q, J=8.4 Hz), 6.88 (5H, m), 7.26 (1H, s). Example 4

Preparation of the compound of general formula IV: Bn = PhCH₂ (l -[3-(benzyloxy)propyl]-5- [(2 )-2-([(17?)-l -phenylethyl] {2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino)propyl]- indoline-7-carbonitrile)

0.60 g (1 ,32 mmol) of l-[3-(benzyloxy)propyl]-5-[(2/?)-2- {[(li?)-l -phenylethyl]amino} propyl]indoline-7-carbonitrile (general formula II: Bn = PhCH₂), 0.72 g (3.34 mmol) of l-(2- bromoethoxy)-2-(2,2,2-trifluoroethoxy)benzene (general formula III: X = Br), 0.37 g (2.68 mmol) of potassium carbonate and 0.27 g (1.63 mmol) of potassium iodide in 3.8 ml of N,N- dimethyl formamide are heated up in a sealed tube to the temperature of 1 10 °C. After 2.5 hours 0.27 g (0.9 mmol) of l -(2-bromoethoxy)-2-(2,2,2-trifluoroethoxy)benzene (general formula III: X = Br) and 0.15 g (1.08 mmol) of potassium carbonate are added. After heating for another 16 hours 0.28 g (0.9 mmol) of l-(2-bromoethoxy)-2-(2,2,2-trifluoroethoxy)- benzene (general formula III: X = Br) and 0.15 g (1.08 mmol) of potassium carbonate are added. The reaction mixture is heated up for 21.5 hours in total. 6 ml of water are added and the mixture is shaken with 3 x 8 ml of ethyl acetate. The combined organic fractions are then washed with 3 x 3 ml of water. The solvent is evaporated and the product is purified with column chromatography, eluent petroleum ether : ethyl acetate 6: 1. 0.398 g (44.8%) of l -[3- (benzyloxy)propyl]-5-[(2 ?)-2-([(li?)-l-phenylethyl] {2-[2-(2,2,2-trifluoromethoxy)- phenoxy]ethyl} amino)propyl]indoline-7-carbonitrile are obtained (general formula IV: Bn = PhCH₂).

•H-NMR (CDC1₃) 0.97 (3H, d, J=6.6 Hz), 1.39 (3H, d, J=6.7 Hz), 1.93- 1.99 (2H, m), 2.23 ( l H, dd, J=13.4, 8.7 Hz), 2.62 (1H, dd, J=13.4, 5.2 Hz), 2.77-3.06 (5H, m), 3.49 (2H, t, J=8,7 Hz), 3.59-3.67 (4H, m), 3.86-4.02 (3H, m), 4.35 (2H, q, J=8.4 Hz), 4.51 (2H, s), 6.62-7.04 (5H, m), 7.21 -7.34 (1 1H, m).

Example 5

a) Preparation of the benzoate of the compound of general formula II: Bn = PhC¾

( l -[3-(benzyloxy)propyl]-5-[(2i?)-2- {[(l/?)-l-phenyl-ethyl]-amino}propyl]-indoline-7- carbonitrile)

2.79 g (8.0 mmol) of l -[3-(benzyloxy)propyl]-5-(2-oxopropyl)indoline-7-carbonitrile (general formula VII: Bn = PhCH₂) are dissolved in 50 ml of dry tetrahydrofuran 1.04 g (8.5 mmol) of benzoic acid are added and 1.1 ml (8.5 mmol) of (R)-l -phenyl ethylamine (formula VIII) are added dropwise. After stirring at the laboratory temperature for 10 minutes 0.10 g (0.5 mmol) of Adams' catalyst is added and the apparatus is rinsed with hydrogen 3 times. Then, the mixture is hydrogenated under slight hydrogen overpressure (ca. 100 Pa) at the laboratory temperature for 24 hours. After removal of the catalyst by filtration and evaporation of the solvent 5.10 g of the raw product of general formula II are obtained in the benzoate form as a light yellow oil.

•H-NMR (CDC1₃) δ 1.1 (3H, d, J=6.4 Hz), 1.59 (3H, d, J=6.6 Hz), 1.95-1.98 (2H, m), 2.46 (lH, dd, J=8.9,13.2 Hz), 2.80-2.98 (4H, m), 3.48-3.67 (6H, m), 4.18-4.25 (lH, m), 4.50 (2H, s), 6.70-6.73 (2H, m), 7.25-7.55 (13H, m), 7.92 (2H, bs), 8.12-8.16 (2H, m). b) Conversion of the benzoate to the hydrochloride of the compound of general formula II: Bn = PhCH₂

2.60 g (4.5 mmol) of l-[3-(benzyloxy)propyl]-5-[(2i?)-2-{[(li?)-l-phenylethyl]amino}propyl]- indoline-7-carbonitrile benzoate are dissolved in 35 ml of acetate, 25 ml of a 10% aqueous solution of sodium carbonate is added and the mixture is stirred at the laboratory temperature for 30 min. The organic phase is separated, the aqueous phase is shaken in 20 ml of ethyl acetate. The solvent is evaporated; the base is obtained in the form of a yellow oil (2.03 g, 99.1 %).

This base (0.56 g, 1.23 mmol) is stirred in 5 ml of ethanolic hydrogen chloride for 30 min, then 5 ml of water are added. The separated product is aspirated. 0.419 g (69.3%>) of beige crystals of l-[3-(benzyloxy)propyl]-5-[(2/i)-2-{[(l/?)-l-phenylethyl]amino}propyl]indoline-7- carbonitrile hydrochloride are obtained.

Ή-NMR (MeOD) £ 1.18 (3H, d, J=6.5 Hz), 1.70 (3H, d, J=6.8 Hz), 1.94 (2H, pent, J=6.6 Hz), 2.44-2.54 (1H, m), 2.91 (2H, t, J=8.6 Hz), 3.08-3.18 (2H, m), 3.54-3.68 (6H, m), 4.49 (2H, s), 4.60 (1H, q, J=6.8 Hz), 6.85 (2H, m), 7.22-7.32 (5H, m), 7.43-7.61 (5H, m).

Example 6

Preparation of the compound of formula I (silodosin; l-(3-hydroxypropyl)-5- [(2i?)-2-({2-[2-(2,2,2-trifluoro-ethoxy)phenoxy]ethyl}amino)propyl]indoline-7-carboxamide) 50 mg (0.10 mmol) of l-(3-hydroxypropyl)-5-[(2 ?)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]- ethyl } amino)propyl]indoline-7-carbonitrile (general formula V: Bn = PhCH₂) are dissolved in 0.5 ml of dimethyl sulfoxide in an inert atmosphere and 0.08 ml of 5M NaOH is added. The mixture is cooled with an ice bath, 0.08 ml (0.80 mmol) of a 30% solution of hydrogen peroxide are added dropwise and the reaction mixture is stirred first under cooling with an ice bath for 10 min, and then at the laboratory temperature for 15 hours. Then, the mixture is cooled with an ice bath again, 0.03 ml (0.3 mmol) of a 30% solution of hydrogen peroxide are added and the mixture is stirred for another 3 hours while it is left to heat up to the laboratory temperature. Then, a solution of sodium pyrosulfite (60 mg) in 1.5 ml of water is added. After stirring for 10 min the mixture is extracted with ethyl acetate and the separated organic phase is then shaken with 2N hydrochloric acid; the separated aqueous phase is, after alkalization, taken up into ethyl acetate again. The combined organic phases are dried (Na₂S0₄). Evaporating the solvent offers 41 mg of the raw product. Silodosin crystallizes by dissolving in ethyl acetate again and cooling (formula I; melting point 99.0-101.7 °C).

'H-NMR (CDC1₃) δ 1.07 (3H, d, J=6.2 Hz), 1.79 (2H, pent, J=6.1 Hz), 2.33 (bs), 2.52 (1H, dd, J=6.8, 13.5 Hz), 2.68 (1H, dd, J=6.5,13.5 Hz), 2.93-3.10 (5H, m), 3.18 (2H, t, J=6.8 Hz), 3.41 (2H, t, J=8.7 Hz), 3.73 (2H, t, J= 5.6 Hz), 4.06-4.12 (2H, m), 4.3 (2H, q, J=8.4 Hz), 6.12 (bs), 6.73 (bs), 6.88-7.06 (5H, m), 7.17 (1H, s). Example 7

Preparation of l-[3-(benzyloxy)propyl]-5-(2-oxopropyl)indoline-7-carbonitrile (general formula VII: Bn = PhCH₂)

3.45 g (9.1 mmol) of l-[3-(benzyloxy)propyl]-5-(2-nitroprop-l-en-l-yl)indoline-7-carbonitrile (XII), 10.7 ml of water, 3.66 g (65.5 mmol) of iron powder and a spoon tip of iron trichloride are charged into a flask. The mixture is heated up to ca. 60°C and 1.5 ml (17.0 mmol) of concentrated hydrochloric acid are added dropwise at this temperature. The mixture is heated up in a bath at the temperature of 90°C for 2.5 hours and is diluted with methanol (10 ml) and chloroform (50 ml). Still being hot, the mixture is filtered over a kieselguhr layer. The organic phase is separated and the aqueous phase is shaken with chloroform (1x 10 ml). The combined organic fractions are then dried with anhydrous sodium sulfate. After evaporation of the solvent the obtained dark oil is purified in a chromatographic column. 1.85 g (5,3 mmol) of the pure product are obtained.

'H-NMR (CDC1₃) δ 1.85-1.96 (2H, m), 2.08 (3H, s), 2.87 (2H, t, J=8.7 Hz), 3.50 (2H, t, J=8.7 Hz), 3.55 (2H, t, J=6.2 Hz), 3.61 (2H, t, J=7.4 Hz), 4.43 (2H, s), 6.83-6.85 (2H, m), 7.18-7.27 (5H, m). Example 8

a) Preparation of benzoate of the compound of general formula II: Bn = PhCH₂ (l -[3-(benzyloxy)pro-pyl]-5-[(2i?)-2- {[(li?)-l-phenyl-ethyl]-amino}propyl]indoline-7- carbonitrile)

2.79 g (8.0 mmol) of l-[3-(benzyloxy)propyl]-5-(2-oxopropyl)indoline-7-carbonitrile (general formula VII: Bn = PhCH₂) are dissolved in 50 ml of dry tetrahydrofuran, 1.04 g (8.5 mmol) of benzoic acid are added and 1.1 ml (8.5 mmol) of (R)-l -phenyl ethylamine (formula III) are added dropwise. After stirring for 10 min at the laboratory temperature 0.10 g (0.5 mmol) of Adams' catalyst are added and the apparatus is rinsed with hydrogen 3 times. Then, hydrogenation is carried out under slight overpressure of hydrogen (ca. 100 Pa) at the laboratory temperature for 24 hours. After removal of the catalyst by filtration and evaporation of the solvent 5.10 g of the raw product of general formula II are obtained in the form of benzoate as a light yellow oil.

' H-NMR (CDC1₃) δ 1.1 (3H, d, J=6.4 Hz), 1.59 (3H, d, J=6.6 Hz), 1.95-1.98 (2H, m), 2.46 ( 1 H, dd, J=8.9,13.2 Hz), 2.80-2.98 (4H, m), 3.48-3.67 (6H, m), 4.18-4.25 (lH, m), 4.50 (2H, s), 6.70-6.73 (2H, m), 7.25-7.55 (13H, m), 7.92 (2H, bs), 8.12-8.16 (2H, m). b) Conversion of the benzoate to the hydrochloride of the compound of general formula II: Bn = PhCH₂

2.60 g (4.5 mmol) of l-[3-(benzyloxy)propyl]-5-[(2i?)-2-{[(l^)-l-phenylethyl]amino} propyl] indoline-7-carbonitrile benzoate are dissolved in 35 ml of ethyl acetate, 25 ml of a 10% aqueous solution of sodium carbonate are added and the mixture is stirred at the laboratory temperature for 30 min. The organic phase is separated, the aqueous phase is shaken with 20 ml of ethyl acetate. The solvent is evaporated; the base is obtained in the form of a yellow oil (2.03 g, 99.1%).

This base (0.56 g, 1.23 mmol) is stirred in 5 ml of ethanolic hydrogen chloride for 30 min and then 5 ml of water are added. The separated product is aspirated. 0.419 g (69.3%) of beige crystals of l -[3-(benzyloxy)propyl]-5-[(2i?)-2-{[(l ?)-l-phenylethyl]amino}propyl]indoline-7- carbonitrile hydrochloride are obtained.

Ή-NMR (MeOD) δ 1.18 (3H, d, J=6.5 Hz), 1.70 (3H, d, J=6.8 Hz), 1.94 (2H, pent, J=6.6 Hz), 2.44-2.54 (1H, m), 2.91 (2H, t, J=8.6 Hz), 3.08-3.18 (2H, m), 3.54-3.68 (6H, m), 4.49 (2H, s), 4.60 (1 H, q, J=6.8 Hz), 6.85 (2H, m), 7.22-7.32 (5H, m), 7.43-7.61 (5H, m). Example 9

Preparation of l-[3-(benzyloxy)propyl]-7-bromoindoline-5-carbaldehyde (general formula X: Bn = PhCH₂)

33.3 g (0.1 1 mol) of l-[3-(benzyloxy)propyl]indoline-5-carbaldehyde (general formula IX: Bn = PhCH₂) are dissolved in 160 ml of acetic acid. Under stirring, 5.5 ml (0.1 1 mol) of bromine are added dropwise, the mixture is stirred at the laboratory temperature for 40 min and then it is poured into a solution of sodium pyrosulfite (4.0 g, 0.02 mol) in 500 ml of cold water. An oil is separated, which is extracted with dichloromethane (3x 150 ml). The combined organic fractions are washed with water (lx 150 ml) and a saturated solution of sodium hydrogen carbonate (1x 100 ml), and dried with anhydrous magnesium sulfate. Evaporating the solvent offers 39.7 g (0.11 mol) of a green-black oil. The product need not be further purified; it is used in the raw condition for the subsequent reaction.

Ή-NMR (CDC1₃) δ 1.95-2.02 (2H, m), 2.99 (2H, t,J=8.8 Hz), 3.53-3.68 (4H, m), 3.81 (2H, t, J=7.5 Hz), 4.51 (2H, s), 7.25-7.41 (6H, m), 7.63 (1H, d, J=1.5 Hz), 9.58 (1H, s).

Example 10

Preparation of l -[3-(benzyloxy)propyl]-5-formylindoline-7-carbonitrile (general formula XI: Bn = PhCH₂)

10 g (0.03 mol)l-[3-(benzyloxy)propyl]-7-bromoindoline-5-carbaldehyde (general formula X: Bn = PhCH₂) are dissolved in 8 ml of N,N-dimethylformamide, 3.12 g (0.03 mol) of copper cyanide are added and the mixture is heated in a nitrogen atmosphere under a reflux condenser in a bath at the temperature of 150°C. After cooling down to ca. 70°C a solution of 5.4 g (0.1 1 mol) of sodium cyanide in 16 ml of water (also at the temperature of ca. 70°C) is added and after stirring for 15 minutes the mixture is diluted with 10 ml of ethyl acetate. The separated aqueous phase is extracted with ethyl acetate (3x 10 ml); the combined organic fractions are washed with a 10% solution of sodium cyanide (lx 10 ml), water (1x 10 ml) and dried with anhydrous sodium sulfate. After evaporation of the solvent 8.64 g of a dark oil are obtained, which are stirred up with 80 ml of diethyl ether. After stirring in an ice bath for 1 hour the separated solid substance is aspirated, washed and dried. 6.6 g (0.02 mol) of a beige powder with the melting point of 64 to 67 °C are obtained.

'H-NMR (CDC1₃) δ 1.97-2.08 (2H, m), 3.01 (2H, t, J=8.7 Hz), 3.63 (2H, t, J=5.9 Hz), 3.72-3.85 (4H, m), 4.50 (2H, s), 7.25-7.37 (5H, m), 7.53 (1H, q, J=1.5 Hz), 7.61 ( 1 H, d, J=1.5 Hz), 9.60 (1H, s). Example 1 1

Preparation of l-[3-(benzyloxy)propyl]-5-(2-nitroprop-l-en-l-yl)indoline-7-carbonitrile (general formula VII: Bn = PhCH₂)

2.94 g (9.2 mmol) of l-[3-(benzyloxy)propyl]-5-formylindoline-7-carbonitrile (general formula XI: Bn = PhCH₂) are dissolved in 16 ml (22 mol) of nitroethane, 0.33 g (4.3 mmol) of ammonium acetate are added and the mixture is heated in a bath at the temperature of 125°C for 4.5 hours. After cooling down, 1.4 g (9.9 mmol) of anhydrous sodium sulfate are added and the mixture is stirred at the laboratory temperature for 30 min. The reaction mixture is diluted with dichloromethane (30 ml) and filtered. After evaporation of the filtrate 3.45 g (9.1 mmol) of the raw product are obtained as a dark red oil.

'H-NMR (CDC1₃) δ 1.89-2.00 (2H, m), 2.38 (3H, s), 2.95 (2H, t, J=8.7 Hz), 3.56 (2H, t, J=6.0 Hz), 3.64 (2H, t, J=9.1 Hz), 3.71 (2H, t, J=7.4 Hz), 4.44 (2H, s), 7.09-7.28 (7H, m), 7.83 (1H, s).

Example 12

Preparation of l-[3-(benzyloxy)propyl]-5-(2-oxopropyl)indoline-7-carbonitrile (general formula VII: Bn= PhCH₂)

3.45 g (9.1 mmol) of l-[3-(benzyloxy)propyl]-5-(2-nitroprop-l-en-l-yl)indoline-7-carbonitrile (general formula XII: Bn = PhCH₂), 10.7 ml of water, 3.66 g (65.5 mmol) of iron powder and a spoon tip of iron trichloride are charged into a flask. The mixture is heated up to ca. 60°C and 1.5 ml (17.0 mmol) of concentrated hydrochloric acid are added dropwise at this temperature. The mixture is heated in a bath at the temperature of 90°C for 2.5 hours and diluted with methanol (10 ml) and chloroform (50 ml). Still being hot, the mixture is filtered over a kieselguhr layer. The organic phase is separated and the aqueous phase is shaken with chloroform (1x 10 ml). The combined organic fractions are then dried with anhydrous sodium sulfate. After evaporation of the solvent the obtained dark oil is purified in a chromatographic column. 1.85 g (5,3 mmol) of the pure product are obtained.

'H-NMR (CDC1₃) δ 1.85-1.96 (2H, m), 2.08 (3H, s), 2.87 (2H, t, J=8.7 Hz), 3.50 (2H, t, J=8.7 Hz), 3.55 (2H, t, J=6.2 Hz), 3.61 (2H, t, J=7.4 Hz), 4.43 (2H, s), 6.83-6.85 (2H, m), 7.18-7.27 (5H, m). Example 13

a) [(3-Chloropropoxy)methyl]benzene

250 ml of dichloromethane, 85 ml (0.71 mol) of benzylbromide and 10 g (0.03 mol) of tetrabutylammonium hydrogen sulfate are added to 50 ml (0.60 mol) of 3-chloro-l-propanol. A solution of sodium hydroxide (150 g, 3.75 mol) in 150 ml of water is added to the mixture under stirring. The mixture refluxed for 22 hours. After cooling down the mixture is diluted with water (100 ml), the layers are separated and the aqueous phase is shaken with dichloromethane (lx 200 ml). The organic fractions are washed with water (lx 200 ml) and subsequently dried with anhydrous sodium sulfate. The solvent is evaporated and the residue is distilled at a reduced pressure. 98.5 g (0.53 mol) of a colourless liquid are obtained, boiling point 75-82 °C (26.64 Pa).

Ή-NMR (CDC1₃) <J2.00-2.10 (2H, m), 3.58-3.69 (4H, m), 4.51 (2H, s), 7.24-7.38 (5H, m). b) 1 -[3-(Benzyloxy)propyl]indoline

26 ml (0.23 mol) of indoline, 30 g (0.22 mol) of potassium carbonate, 28 g (0.17 mol) of potassium iodide and 625 ml of N,N-dimethylformamide are charged into a flask equipped with a reflux condenser and a calcium drying tube. 30 g (0.16 mol) of [(3-chloropropoxy)- methyljbenzene are added to the mixture dropwise under stirring and the mixture is heated up in a bath at the temperature of 130°C for 3.5 h. Then, another 26 g (0.19 mol) of potassium carbonate are added and 28 g (0.15 mol) of [(3-chloropropoxy)methyl]benzene are added dropwise. The mixture is maintained at 130°C for further 22 hours. After cooling down inorganic salts are removed by filtration and the solvent is evaporated. 400 ml of dichloromethane are added to the residue and the mixture is filtered again. The filtrate is washed with water (lx 100 ml), brine (lx 100 ml), and dried with anhydrous sodium sulfate. After evaporation of the solvent and purification in a chromatographic column 43 g (0.16 mol) of the product are obtained in the form of a yellow oil.

•H-NMR (CDC1₃) δ 1.84-1.95 (2H, m), 2.93 (2H, t , J=8.3 Hz), 3.17 (2H, t, J=7.1 Hz), 3.31 (2H, t, J=8.3 Hz), 3.57 (2H, t, J=6.2 Hz), 4.50 (2H, s), 6.45-6.48 (1H, m), 6.58-6.64 (1H, m), 7.01-7.06 (2H, m), 7.24-7.34 (5H, m). c) l-[3-(Benzyloxy)propyl]indoline-5-carbaldehyde (general formula IX: Bn = PhCH₂)

155 ml of N,N-dimethylformamide are charged into a flask equipped with a calcium drying tube, cooled down to 0 °C, and then 16.3 ml (0.17 mol) of phosphoryl chloride are added dropwise during 10 minutes. The mixture is stirred at a temperature of 0 to 5°C for 50 min, then a solution of l-[3-(benzyloxy)propyl]indoline (38.9 g, 0.15 mol) in 250 ml of tetrahydrofuran is added dropwise during 30 min. The reaction mixture is still stirred under cooling for 40 min and then at the laboratory temperature for 20 hours. The reaction is terminated by addition of 250 ml of water (spontaneous heating up to ca. 35°C will occur); after stirring for 4 hrs 250 ml of ethyl acetate are added, the layers are separated and the aqueous phase is extracted with ethyl acetate (lx 250 ml). The combined organic fractions are washed with water (1x 250 ml), a saturated solution of sodium hydrogen carbonate (2x 250 ml) and brine (lx 150 ml). After drying with anhydrous sodium sulfate and evaporation of the solvent the raw product is chromatographically purified. 33.9 g (0.1 1 mol) of a red oil are obtained.

'H-NMR (CDC1₃) δ 1.87-1.93 (2H, m), 3.02 (2H, t, J=8.6 Hz), 3.35 (2H, t, J=7.0 Hz), 3.53 (2H, t, J=5.9 Hz), 3.57 (2H, t, J=8.9 Hz), 4.49 (2H, s), 6.39 (1H, d, J=8.6 Hz), 7.25-7.35 (5H, m), 7.51 -7.54 (2H, m), 9.64 (1H, s).

Claims

C L AI M S

A method of manufacturing optically pure or optically enriched silodosin of formula I

and of its pharmaceutically acceptable salts,

in which a secondary amine of general formula II

wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group,

(a) is N-alkylated with an alkylating agent of general formula III

wherein X denotes a good leaving group, such as a halogen or an alkane sulfonyloxyl group RS0₂0 or an arene sulfonyloxyl group ArS0₂0, R means an alkyl group with 1 to 4 carbon atoms and Ar is a substituted or unsubstituted phenyl group;

(b) the obtained tertiary amine of general formula IV

wherein Bn is as defined above,

is hydrogenolyzed with hydrogen on a metal catalyst;

(c) and the resulting nitrile of formula V

wherein Bn is as defined above,

is hydrolyzed by treatment with alkaline agents;

(d) optionally, additional O-debenzylation of the amide-ether of general formula VI

wherein Bn is as defined above,

with dealkylating agents is carried out; and, if desired, the obtained silodosin is transformed to the respective salts by treatment with pharmaceutically acceptable acids.

2. The method according to claim 1, characterized in that a secondary amine of general formula II

wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group,

is

(a) N-alkylated with an alkylating agent of eneral formula III

(III) wherein X denotes a good leaving group, such as a halogen or an alkane sulfonyloxyl group RSO₂O or an arene sulfonyloxyl group ArS0₂0, R means an alkyl group with 1 to 4 carbon atoms and Ar is a substituted or unsubstituted phenyl group;

in the presence of a base, in an inert organic solvent selected from the group consisting of carboxamides, N-methyl pyrrolidone, CrC₄ alcohols and dimethyl sulfoxide, at temperature from 50°C to the boiling point of the mixture, preferably at 75-125°C, optionally in the presence of an alkali metal iodide (Step A);

(b) the obtained tertiary amine of general formula IV

wherein Bn is as defined above, is selectively N-hydrogenolyzed with hydrogen on a metal catalyst at a pressure of 0.1 -5 MPa or by means of ammonium formate, in an inert organic solvent selected from the group consisting of C1 -C3 alcohols, cyclic ethers, ethyl acetate and toluene and their mixtures, at temperatures of 10-60°C;

(c) and the resulting nitrile of formula V

wherein Bn is as defined above,

is hydrolyzed by treatment with alkaline agents such as alkali metal hydroxides, optionally in the presence of hydrogen peroxide, in polar solvents such as methanol, ethanol, glyme or diglyme or dimethylsulfoxidu, at temperatures of from -10°C to the boiling point of the mixture; and

(d) the amide-ether of general formula VI

wherein Bn is as defined above,

is subjected to O-debenzylation with hydro genolytic or trialkylhalide dealkylating agents; and, if desired, the obtained silodosin is transformed to the respective salts by treatment with pharmaceutically acceptable acids.

3. The method according to claim 2, characterized in that the alkylating agent of formula III in step (a) is a halide wherein X is a halogen, or an alkane sulfonate wherein X = OS0₂R or an arene sulfonate wherein X = OS0₂Ar, and is used in an amount of 1-7 equivalents, preferably 1.5-4 equivalents, in the presence or absence of an alkali metal iodide.

4. The method according to claims 2 and 3, characterized in that the base in step (a) is an inorganic base selected from potassium and sodium carbonate, or a hindered organic base such as diisopropylethylamine, and is used in an amount of 0.5-8 equivalents.

5. The method according to claims 2-4, characterized in that a chloride, bromide, alkanesulfonate or arenesulfonate of formula III is used in step (a), in an amount of 0.1 to 2 equivalents in dimethyl formamide at a temperature of 90-125°C.

6. The method according to claims 2-5, characterized in that the N-hydrogenolysis in step (b) is carried out with hydrogen on Pd/C in the environment of methanol, ethanol or isopropyl alcohol, or a mixture thereof with water, at a pressure of 0.1-3 MPa, at a temperature of 20- 50°C.

7. The method according to claims 2-6, characterized in that the hydrolysis in step (c) is carried out with alkali hydroxides in the presence of hydrogen peroxide in dimethyl sulfoxide at a temperature of from - 10 to 100°C, preferably at 0-40°C.

8. The method according to claims 2-7, characterized in that the hydrogenolytic agent in step (d) is hydrogen on a metal catalyst selected from palladium or platinum and the O- debenzylation is carried out in inert solvents selected from the group consisting of ethanol, methanol, 2-methyltetrahydrofuran, tetrahydrofuran and ethyl acetate and their mixtures, at temperatures of 10-50°C.

9. The method according to claims 2-8, characterized in that the O-debenzylation in step (d) is carried out with hydrogen on Pd/C in the environment of methanol, ethanol or ethyl acetate, or of a mixture thereof.

10. The method according to claims 2-7, characterized in that the hydrogenolytic agent in step (d) is a trialkyl silyl halide agent and the O-debenzylation is carried out in an inert solvent such as dichloromethane, chloroform or toluene, at temperatures of from -5 to +40°C, preferably at 5-25°C.

1 1. The method according to claim 1 , characterized in that

(a) a secondary amine of general formula II

wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group,

is N-alkylated with an alkylating agent of general formula III

wherein X denotes a good leaving group selected from the group consisting of a halogen, an alkane sulfonyloxyl group RS0₂0 and an arene sulfonyloxyl group ArS0₂0, R means an alkyl group with 1 to 4 carbon atoms and Ar is a substituted or unsubstituted phenyl group, in the presence of a base, in an inert organic solvent selected form the group including carboxamides, N-methyl pyrrolidone, lower alcohols and dimethyl sulfoxide, at the temperatures of from 50°C to the boiling point of the mixture, optionally in the presence of an alkali metal iodide;

(b) the obtained tertiary amine of general formula IV

wherein Bn is as defined above, is subjected to ON-hydrogenolysis with hydrogen on a metal catalyst in the presence of strong acids, such as hydrochloric acid, sulfuric acid or methanesulfonic acid, at a pressure of from 0.1 to 5 MPa in an inert organic solvent;

(c) the resulting nitrile of formula V

is subjected to hydrolysis by treatment with alkali metal hydroxides, optionally in the presence of hydrogen peroxide in polar solvents such as methanol, ethanol., glyme or diglyme, or dimethyl sulfoxide, at a temperature of from -10°C to the boiling point of the mixture; and, optionally, converted to the respective salts by treating with pharmaceutically acceptable acids.

12. [3-(Benzyloxy)propyl]-5-[(2/?)-2-([(l/?)-l-phenylethyl] {2-[2-(trifluoromethoxy)- phenoxy]ethyl}amino)propyl]indoline-7-carbonitrile of general formula IV

wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group,

13. l -[3-(Benzyloxy)propyl]-5-[(2i?)-2-{[(l/?)-l-phenylethyl]amino}propyl]indoline-7- carbonitrile of general formula II

wherein Bn denotes a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, or the benzhydryl or trityl group,

14. Use of the compound of general formula IV in manufacturing silodosin of formula I.

15. Use of the compound of general formula II in the manufacture of silodosin.